The present invention relates to the use of the .alpha.-conotoxin MII to treat disorders that are caused by the action of nicotine stimulating nicotinic acetylcholine receptors (nAChRs). When nicotine binds to certain subtypes of nAChRs it induces the release of dopamine. The .alpha.-conotoxin MII has now been found to be a specific neuronal nAChR antagonist and can limit nicotine stimulated dopamine release. Cigarette smoke contains nicotine, which acts upon nAChRs resulting in dopamine release, which is effectively a reward. Treatment with .alpha.-conotoxin MII will block the nicotinic receptors thereby preventing the release of dopamine and will block the reward. Consequently .alpha.-conotoxin MII can be used to aid persons to quit smoking.
A second aspect of the invention is that .alpha.-conotoxin MII is useful for the treatment of various psychoses, e.g., schizophrenia and mood disorders. Presently the standard treatment for psychosis is to block the post-synaptic dopamine recognition. The equivalent effect is be achieved by blocking an earlier step, specifically, by blocking the presynaptic release of dopamine. .alpha.-Conotoxin MII is effective at preventing the presynaptic release of dopamine because it is a nAChR antagonist.
The publications and other materials used herein to illuminate the background of the invention, or to provide additional details respecting the practice, are incorporated by reference and for convenience are respectively grouped in the appended List of References.
Neuronal nicotinic acetylcholine receptors have been implicated in the treatment or pathophysiology of several neuropsychiatric disorders including Alzheimer's disease (Nordberg et al., 1990; Nordberg et al., 1989), Parkinson's disease (Grandinetti et al., 1994; Janson et al., 1988; Reavill, 1990), Tourette's syndrome (Sandberg et al., 1988; Sandberg et al., 1989) and schizophrenia (Adler et al., 1993; Luntz-Leybman et al., 1992). In addition, nicotine, a psychoactive constituent of tobacco smoke, reinforces smoking behavior through its effects on nAChRs (Stolerman and Jarvis, 1995). The central effects of nicotine are complex and appear to be mediate by several nAChR subtypes, but it is not known which subtype(s) is responsible for the reinforcing effects of nicotine.
Neuronal nicotinic acetylcholine receptors are believed to be heteropentameric ion channel complexes generally requiring at least two different subunits (an .alpha. and a .beta.). Molecular data indicate that in the mammalian central nervous system there exists a large number of different nAChR subunits. To date, seven different .alpha. subunits (.alpha.2-.alpha.7, .alpha.9) and three different .beta. subunits (.beta.2-.beta.4) have been defined by cloning.
Currently available neuropsychiatric medications work primarily by blocking neurotransmission through postsynaptic receptor antagonism or by blocking neurotransmitter re-uptake or catabolism (Schatzberg et al., 1995). While postsynaptic nAChRs have been recognized for some time, more recent data have demonstrated the presence of presynaptic neuronal nAChRs. Agonist stimulation of presynaptic nAChRs induces neurotransmitter release. Nicotinic agonists have been shown to elicit the release of several different neurotransmitters, including dopamine from striatum and frontal cortex (El-Bizri and Clarke, 1994; Grady et al., 1992; Rapier et al., 1988); norepinephrine from hippocampus (Clarke and Reuben, 1996; Rowell and Winkler, 1984; Sacaan et al., 1995; Wilkie et al., 1993); glutamate from cortex, medial habenula nucleus and hippocampus (McGehee and Role, 1995; Vidal and Changeux, 1993; Gray et al., 1996); GABA from interpeduncular nucleus (Mulle et al., 1991) and acetylcholine for cortex and hippocampus (Lapchak et al., 1989; Rowell and Winkler, 1984).
In addition, it appears that distinct subtypes of presynaptic nAChRs regulate the release of different neurotransmitters. For example, nicotine-stimulated glutamate and acetylcholine release are blocked by .alpha.-bungarotoxin suggesting that these nAChRs include an .alpha.7 subunit (McGehee and Role, 1995). In contrast, nicotine-stimulated dopamine release is not blocked by .alpha.-bungarotoxin (Grady et al., 1992). Furthermore, the nAChRs modulating norepinephrine release pharmacologically differ from those modulating the release of glutamate, acetylcholine or dopamine (Clarke and Reuben, 1996; Sacaan et al., 1995).
The possibility of selectively modulating the presynaptic release of specific neurotransmitters has significant therapeutic applications. For example, current antipsychotic medications inhibit dopamine signaling by blocking postsynaptic dopamine receptors. Block of presynaptic nAChRs will attenuate but not abolish dopamine signaling, a result which leads to antipsychotic effects but with fewer sides than complete postsynaptic dopamine receptor blockade. Another example of a therapeutic application is tobacco addiction. Studies of nicotine self-administration in animal models suggest that block of nAChRs decreases the reinforcing properties of nicotine.
Despite the importance of nAChRs that modulate dopamine release, the particular subtypes which underlie this release have been difficult to determine despite substantial investigation. This difficulty is due in part to the lack of subtype-specific ligands. The use of the newly isolated .alpha.-conotoxin MII, a specific neuronal nAChR antagonist to examine nAChRs involved in nicotine-stimulated neurotransmitter release is described here.